UA54393C2 - Benzimidazole compounds, pharmaceutical composition containing them, and a method for treatment of gaba-receptor complex of central nervous system disorders sensitive to positive modulation - Google Patents

Abstract

The present patent application discloses compounds having formula (I) or a pharmaceutically acceptable salt thereof or an oxide thereof, wherein R3 is (II), wherein А, В and D each is CH, or one or two of А, В and D is N and the others are CH; R11 is phenyl, benzimidazolyl, or monocyclic heteroaryl all of which may be substituted one or more times with substituents selected from alkyl, alkoxy, phenyl, halogen, СF3, ammo, nitro, cyano, acyl, acylamino, phenyl and monocyclic heteroaryl; and one of R6 and R7 is hydrogen and the other is furanyl or isoxazolyl each of which may be substituted one or more times with substituents selected from halogen, alkyl, alkoxy and phenyl. The compounds are useful for the treatment of various central nervous system disorders such as epilepsy and other convulsive disorders, anxiety, sleep disorders and memory disorders.

Description

Description of the invention

The invention relates to new benzimidazole compounds, pharmaceutical compositions containing these compounds, 2 methods of treatment with them, as well as methods of obtaining such benzimidazole compounds. The novel compounds are useful in the treatment of such diseases and disorders of the central nervous system sensitive to modulation

GABA-receptor complexes, such as anxiety, sleep disorders, memory, or epileptic or other convulsive disorders.

Gamma-aminobutyric acid (GABA) receptors, GABA d-receptors, are the most common inhibitory receptors in the mammalian brain. GABA receptors have a micromolecular heteropentamer structure (combinations of o, vd and u/5 protein subunits). Some subtypes of such GABA d-receptors are described in the practice of modern molecular biology.

Each GABA receptor complex includes a channel for chloride ions, which regulates the transfer of these ions across the neuron membrane, and a set of recognition sites for such small modulatory molecules as benzodiazepines, barbiturates, picrotoxins, and some steroids. When GABA interacts with its receptor, an ion channel opens, chloride transport increases, the membrane hyperpolarizes and the cell becomes less sensitive to excitation. This GABA-induced ion transfer can be regulated by various agents, including interacting with benzodiazepine receptors or recognition sites.

Agents that bind to or interact with the modulating sites of such GABA-receptor complexes, such as benzodiazepine receptors, can have either a potentiating effect on the action of GABA, for example, a positive modulation of the action of the receptor (agonists, partial agonists), a weakening effect on the action of GABA, for example, negative modulation of receptor action (inverse agonists, partial inverse agonists), or they can block the effect of agonists and inverse agonists following competitive blocking (antagonists or ligands devoid of intrinsic activity). with

Agonists usually exhibit muscle relaxant, hypnotic, sedative, tranquilizing, and/or anticonvulsant effects, while inverse agonists exhibit proconvulsant, antiintoxicant, and anxiolytic effects.

Partial agonists are characterized as tranquilizing compounds, but without or with reduced muscle relaxant, hypnotic, and sedative effects, while inverse agonists are considered useful as mental enhancers. at

Over the past decade, a number of compounds belonging to different types and having affinity for benzodiazepine receptors have been synthesized. However, although the benzodiazepine receptor sites are still considered very attractive for biological interactions with the central nervous system (CNS) for the treatment of a variety of brain disorders and diseases, almost all previously synthesized compounds acting on these receptor sites have been recognized in clinical trials. unsuitable due to undesirable side effects.

According to the invention, new benzimidazole compounds interacting with the benzodiazepine receptor are proposed

GAMKA-receptor complex. The compounds of the invention are useful modulators of GABA d-receptor complexes.

The object of the invention is to propose new compounds of benzimidazole and their pharmaceutically acceptable salts with acids, which are useful in the treatment of disorders, diseases or ailments of the central nervous system, which are sensitive to the modulation of GABA-receptor complexes, especially their positive modulation. The second object of the invention is pharmaceutical formulations containing new benzimidazole compounds useful for the above-mentioned purpose. Another object of the invention is a new method of treatment using new benzimidazole compounds.

A further task is the method of manufacturing new pharmaceutical formulations.

Additional tasks will be apparent from the description below, and others will be known to those skilled in the art. o The invention, together with another, includes the following, alone or in combination: A compound having the formula: M s yu khz s" y or its pharmaceutically acceptable salt or oxide, where 3.

AH,

Oh, where each A, B and 0 is CH, or one or two A, B and 0 are M, and the others are CH;

B"! - phenyl, benzimidazole or monocyclic heteroaryl, each of which can be substituted by one or more than 60 substituents selected from alkyl, alkoxyl, halogen, CEz, and lino-, nitro-, cyano-, acyl, acylamino groups, phenyl, and also monocyclic heroaryl, and one of B5 and B is hydrogen, the other is furanyl or isoxazolyl, each of which may be substituted one or more times with substituents selected from halogen, alkyl, alkoxy, and phenyl; the above compound, which is 65 1-( 3-(1-midazolyl)phenyl)-5-(3-furanyl)benzimidazole,

1-(3-(2-lethyl-1-imidazolyl)phenyl)-5-(3-furanyl)benzimidazole, 1-(3-(5-pyrimidinyl)phenyl)-5-(3-furanyl)benzimidazole, or their a pharmaceutically acceptable salt or oxide; a pharmaceutical formulation comprising an effective amount of any of the above compounds or a pharmaceutically acceptable salt or oxide thereof together with at least one pharmaceutically acceptable carrier or diluent; the use of any of the above-mentioned compounds for the manufacture of drugs for the treatment in living beings, including humans, of disorders or diseases sensitive to positive modulation of GABA d-receptors of their complexes of the central nervous system; 70 use of any of the above-mentioned compounds for the manufacture of drugs for the treatment in living beings, including humans, of disorders or diseases sensitive to positive modulation of GABA d-receptor complexes of the central nervous system; use of any of the above compounds for the manufacture of medicaments for the treatment of disorders or diseases selected from anxiety, sleep disorders, memory disorders, epilepsy and any other convulsive disorders; a method of treatment in living creatures, including humans, of disorders or diseases sensitive to positive modulation of GABA d-receptor complexes of the central nervous system, which includes the use by each living creature, including humans, when it needs it, of a therapeutically effective amount of any of the above-mentioned compounds. the above-mentioned method for the treatment of disorders or diseases sensitive to positive modulation of GABA-receptor complexes of the central nervous system; the above method for the treatment of restlessness, sleep disorders, memory disorders, epilepsy and any other convulsive disorders; as well as the above method in which the active ingredient is used in the form of a pharmaceutical formulation in which it is together with a pharmaceutically acceptable carrier or excipient. with

Halogen is fluorine, chlorine, bromine or iodine.

Alkyome means a group containing a straight or branched chain of 1 to 8 carbon atoms, or i) cycloalkyl with 3 to 7 carbon atoms, which includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; methyl, ethyl, propyl, isopropyl, t-butyl are preferred. с зо "Alkoxyl" means -O-alkyl, where alkyl is designated above.

Acyl means -(C-O)-H or -"C-O)-alkyl, where alkyl is indicated above. Me

The acylamino group is understood as acyl-MH-, where acyl is indicated above. with

The amino group is understood as -MH", -MH-alkyl, or -M-(alkyl)2, where alkyl is indicated above.

Monocyclic heteroaryl is a 5- or b-membered monocyclic heterocyclic group. Such monocyclic and heterocyclic groups include, for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2- yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, 1,2,4-thiadiazol-Z-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-Z-yl, 1,2,5-oxadiazol- 4-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 1-imidosalyl, 2-imidosalyl, 4-midozalyl, 1-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, « 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl , eta) with 2-pyrazinyl, 1-pyrazolyl, 2-pyrazolyl and 4-pyrazolyl.

Examples of pharmaceutically acceptable salts with acids include salts of such inorganic and organic acids as, for example, hydrochloric, hydrobromic, phosphate, nitrate, perchlorate, sulfate, citric, lactic, tartaric, maleic, fumaric, mandelic, benzoic, ascorbic, cinnamic, benzenesulfonic,

Methanesulfonic, stearic, amber, glutamic, glycolic, toluene-p-sulfonic, formic, malonic, c naphthalene-2-sulfonic, salicylic and acetic.

Other acids such as oxalic acid are not pharmaceutically acceptable, but may be useful as intermediates in the preparation of compounds of the invention and pharmaceutically acceptable acid salts. oo Such salts are obtained in a manner well known to specialists.

The compounds according to the invention can be solvated or not in such pharmaceutically acceptable solvents as water, ethanol and the like. In general, according to the object of the invention, solvated and non-solvated forms of this are considered equivalent.

Some of the compounds according to the invention are (w) and (-) as well as racemic. Racemic forms can be separated into optical antipodes in known ways, for example, by separation of their diastereoisomeric salts with optically active acids followed by release of optically active amines by treatment with bases.

Other methods of separating racemates into optical antipodes are based on chromatography on an optically active (F) carrier. The racemic compounds according to the invention can therefore be separated into their optical antipodes, for example by fractional crystallization of the α- or I-" tartrates, millidelates or camphorsulfonates. The compounds according to the invention can also be separated into their diastereoisomeric amides, obtained by reaction with such optically active or activated carboxylic acids as derivatives of (Ж) or (-) phenylalanine (Ж) or (-) phenylglycine, (Ж) or (-y camphanic acid), or the formation of diastereoisomeric carbamates by reaction with optically active chloroformates or similar to them

It is possible to use additional known and obvious methods for separating optical isomers even to ordinary specialists. These methods are considered by U. Dadzez, A. SoMeyi 5Z. MUishp in "Epapiteg5, Kasetay(ez apa 65 Kezoishiopvg), UOip Umieu ippa Bopz, Mem HogKk (1981).

The compounds according to the invention can be obtained in various ways.

The compounds according to the invention and their pharmaceutically acceptable derivatives can also be obtained by any methods known to those skilled in the art of obtaining compounds of similar structure, as indicated below in the examples.

Fig. 1 - 6 describe methods of making compounds according to the invention, in which E.5 -furanyl or isoxazolyl, and B! - hydrogen Compounds according to the invention, in which c is furanyl or isaxazolyl, and b is hydrogen, can be obtained similarly.

The starting materials for carrying out the method described according to the invention are known or can be obtained from commercially available chemicals.

The products of the reactions described here were isolated by such conventional techniques as extraction, crystallization, distillation, chromatography, and the like. 4-Aminobutyric acid (GABA) is the main inhibitor of neuroconductivity, and has been shown to affect both the central and peripheral nervous systems. Currently, two types of GABA receptors are known - GABA and

GABAcrB receptors. Recent studies in molecular biology have demonstrated that GABA d-receptors can be divided into several subreceptors associated with the selective and/or partial pharmacological action observed with some benzodiazepine receptor ligands, which is opposite to the nonselective action observed for such classical benzodiazepine ligands. receptors, such as diazepam. Activation

of GABA receptors leads to changes in the membrane potential (hyperpolarization). β-GABA receptors are linked to chloride transport through coupled and coupled chloride channels, while activation of GABA in the β-receptor indirectly affects potassium and calcium channels as well as modifies the second binding product.

GABA-recognizing sites can be activated by GABA, muscimol, and, for example, isoguacin, but not by such GABA scionists as, for example, baclofen. The modulated GABA-recognizing site on the benzodiazepine receptor site can be marked by ZN-flunitrazepam. Thus, the affinity of various potential ligands to the sites of benzodiazepine receptors can be determined by the ability of the tested compounds to replace ZH-flunitrazepam. with

Tissue preparations: The preparations were prepared at 0 - 4"C, unless otherwise indicated. 150 - 200g of the cerebral cortex of male d) Uiviag rats were homogenized for 5 - 10 seconds in 20 ml of Ttiz-HCI (ZOmMM, pH7.4) in an Oiga-Tytakh homogenizer, Suspension centrifuged at 270004 for 15 min. and washed the sediment three times with buffer, centrifuging at 270009 for 15 min. The washed sediment was homogenized in 20 ml of buffer and incubated in a water bath at 37"С 30°C. to remove its own GABA, and then centrifuged 1 Ohv. at 270009. Next, the sediment was homogenized in a buffer and centrifuged at 10 rpm. at 270004. o

The resulting precipitate was resuspended in 30 ml of buffer and the preparation was frozen and stored at -202C. Gee!

Analysis: The membrane preparation was melted and centrifuged for 1 Okhv. at 27"C and 270009. The resulting precipitate was resuspended in 50 ml of Tgiz-citrate, pH 7.1 (500 g of buffer per 1 g of original tissue) and was further used for determination of binding. About 0.5 ml of the tissue preparation was added to 25 ml of the test solution, was mixed with 25 ml of ZN-FNIZ (final concentration of TNM) and incubated for 4 hours at 27 C. Nonspecific binding was determined,

Zo using clonazepam (final concentration of 1nM). After incubation, bml of ice-cooled buffer was added to the samples, transferred to M/paytap SBR/C glass vacuum filters and immediately washed with ml of ice-cooled buffer. Determination of radioactivity on the filters was carried out as usual - by counting scintillations in the liquid. Specific binding was taken to be the difference between general and non-specific binding. "

The determined values were calculated as ICeo (concentration in nM) of the test substance, which inhibits the specific 7th binding of ZN-FNZ by 5095. The results of the test of the selected compounds according to the invention are clear from the table below. from 5 p.m.»

If possible, for use in therapy, the compound according to the invention can be used without impurities, but the presence of active ingredients in the form of a pharmaceutical formulation is desirable.

Th) 20 According to the invention, a pharmaceutical formulation is proposed, which contains a compound according to the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and because preventive ingredients. The carrier(s) must be "suitable" in terms of compatibility with the other ingredients of the formulation and not harm the recipient.

Pharmaceutical formulations include suitable for oral, rectal, nasal, local (including 29 oral and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and (FI intravenous) use, or in in a form suitable for use in the form of inhalation or injection.

The compound according to the invention, together with a conventional carrier, carrier or diluent, can thus be prepared in the form of pharmaceutical formulations and their unit doses, and applied in such a solid state as tablets or filled capsules, or liquid - in the form of solutions, suspensions , emulsions, elixirs or 60 capsules filled with them - for oral use, in the form of suppositories for rectal chewing, or in the form of sterile solutions for injections for parenteral (including subcutaneous) use. Such pharmaceutical formulations and unit doses thereof may include conventional ingredients in conventional proportions, with or without additional active compounds or constituents, and such unit doses may contain any suitable amount of active ingredient according to the level of the prescribed daily dose. Formulations containing one (1) mg of active ingredient or, more broadly, from 0.01 to 100 mg per tablet may respectively represent a unit dose.

The compounds of the invention can be used in a wide range of doses for oral and parenteral use. Those skilled in the art will appreciate that the following dosages may include as an active ingredient a compound according to the invention or a pharmaceutically acceptable salt of a compound according to the invention.

Pharmaceutically acceptable carriers for the manufacture of compounds according to the invention of pharmaceutical formulations can be solid or liquid. Solid forms of drugs include powders, tablets, wafers, capsules (including starch), dragees, suppositories, and dispersible granules.

The solid carrier may consist of one or more substances that may also serve as diluents, 7/0 flavorings, solubilizers, lubricants, suspending, binding, preserving, tablet disintegrating agents, or encapsulating material.

In powders, the carrier is a finely ground substance mixed with a finely ground active ingredient.

In tablets, the active component is mixed in a suitable proportion with a carrier having the necessary binding properties, and the mixture is given the desired shape and size.

Powders and tablets preferably contain from one to seventy percent of the active compound. Suitable carriers are magnesium carbonate and stearate, talc, sugar, lactose, peptin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, and the like. The term "preparation" includes a formulation with an active compound and an encapsulating material as a carrier, forming a capsule in which the active ingredient, with or without carriers, is surrounded by a combined carrier. The same applies to wafers and tablets. Tablets, powders, wafers, capsules and dragees can be used as solid forms for oral administration.

In the manufacture of suppositories, a low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter is first melted, and then the active component is homogenized by dispersing it during mixing.

The molten homogenized mixture is then poured into a mold of a suitable size and solidified by cooling. with

Formulations suitable for vaginal use can be made as pessaries, tampons, creams, gels, pastes, foams or aerosols, which in addition to the active ingredient contain such carriers as are well known to those skilled in the art. (8)

Liquid formulations include solutions, suspensions and emulsions, for example in aqueous or aqueous propylene glycol solutions. For example, liquid formulations for parenteral injection can be made on the basis of a water-propylene glycol solution. Compounds according to the invention can be prepared for parenteral administration (for example, injection, including bolus injection or prolonged infusion) in the form of single doses in the form of ampoules, pre-filled Me syringes, small volume infusions or / reusable containers with added preservatives. with

Formulations can be suspensions, solutions or emulsions in an oil or aqueous medium and contain such form-forming agents as suspending, stabilizing and/or dispersing agents. On the other hand, the active ingredient can be a powder obtained before use under aseptic conditions from a sterile solid, or can be lyophilized from a solution to be combined with a suitable medium, such as sterile pyrogen water.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water with the addition, if desired, of suitable dyes, flavors, thickeners and stabilizers.

Aqueous suspensions suitable for oral use can be prepared by dispersing the active ingredient in water with such thickening materials as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents well known to those skilled in the art.

І Also included are solid recipes that can be converted into і immediately before use. liquid compositions for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations may contain, in addition to the active ingredient, dyes, flavors, thickeners, stabilizers, buffers, artificial and natural sweeteners, dispersants, solubilizers, etc. c For local application to the epidermis, compounds according to the invention can be applied in the form of ointments, creams, lotions, or as transdermal plaques. Ointments and creams can be made on a water or oil basis with the addition of suitable thickening and/or gelling agents. Lotions can be made on a water or oil basis, usually they contain one or more emulsifying, stabilizing, dispersing, suspending, thickening or coloring agents. and, Formulations suitable for topical use in the mouth include tablets containing the active agent in a 4) flavor base, usually sucrose with gum arabic or tragacanth; lozenges contain the active ingredient in such an inert base as gelatin and glycerin, as well as sucrose and gum arabic; and mouthwashes contain the active ingredient in a P zidat liquid carrier.

Solutions or suspensions are injected directly into the nasal cavity by appropriate means, for example, a dropper, a pipette or in a sprayed state. Formulations can be offered in single or multiple dosages. In the latter case, droppers or pipettes can be used to receive a suitable predetermined volume of solution or suspension by the patient. In the case of spraying, they can be used by means of metered spraying under pressure. 60 Application into the respiratory tract can also be accomplished by aerosol formulations in which the active ingredient is used in pressurized packages with a suitable propellant such as chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, and other suitable gases. Aerosol is usually may contain surfactants such as lecithin. The dosage of the drug can be adjusted by a dosing valve. 65 Alternatively, the active ingredients can be used as dry powders, for example in the form of a powder mixture of the compound in a suitable powder base such as lactose, starch, and such derivatives , such as hydroxypropylmethylcellulose for and polyvinylpyrrolidine (PVP). Usually powder carriers form a gel in the nasal cavity. Powder formulations can be presented in the form of unit doses, for example, in capsules or cartridges, for example, from gelatin, or in a blister pack, from which the powder can be used by means of inhalation.

In formulations intended for inhalation, including intranasal formulations, the particle size of the compound is small, on the order of, for example, 5 microns or less. Particles of this size can be obtained by methods known to those skilled in the art, for example, by micronization.

If desired, formulations supporting the release of the active ingredient can be used. 70 Pharmaceutical formulations are preferably in the form of unit doses, whereby the formulation is divided into unit doses containing a suitable amount of the active ingredient. Unit doses can be packaged, the package holds such discrete quantities of the drug as tablets, capsules and powders in glasses or ampoules. A single dose can also be a capsule, tablet, wafer, dragee, or consist of several such units in a packaged form.

The preferred formulations are tablets and capsules for oral administration and liquids for intravenous administration.

The compounds according to the invention are particularly useful in the treatment of disorders or diseases of animal organisms due to their affinity for the benzodiazepine binding sites of GABA receptors. These properties make the compounds of the invention particularly useful in the treatment of convulsions, anxiety states, sleep and memory disorders, and other disorders sensitive to GABA d-receptor modulation. Accordingly, the compounds of the invention can be administered to individuals, including humans, in need of treatment, alleviation or elimination of a disorder or disease associated with GABA d-receptors. This especially applies to convulsions, anxiety states, sleep and memory disorders.

Suitable daily doses are 0.01 - 10Omg, 0.1 - 5Omg, and especially 0.1 - ZOmg, depending, as usual, on the applied method of treatment, the form of administration, the determination of what the administration is aimed at, and the weight of the recipient. and in addition, the choice and experience of the doctor or veterinarian.

The following examples illustrate the invention, but do not limit it. Compounds according to the invention, (8) are prepared as in the following examples, presented in tables 1 - 2 on p. 35 - 36.

Example .1. 4-fluoro-1-iodo-3-nitrobenzene (1c). A suspension of 100 g (0.64 mol) of 4-fluoro-3-nitroaniline in 100 ml of concentrated sodium hydroxide was cooled to -20°C. With stirring, solution 48 was added. 6 g (0.7 mol) of sodium nitrite in 100 ml of water, maintaining the temperature below -157 C, the mixture was then stirred for 45 minutes at -207 C -(-157 C). A solution of 132.8 g (0.8 mol) of iodide was added to the resulting Me solution potassium in 260 ml of water so that the temperature does not exceed 0"C. The solution was stirred until the release of nitrogen stopped. 200 ml of 0.1 M aqueous sodium sulfite was added to the mixture and extracted with diethyl ether. The ether extract was washed twice with 0.1 M sodium hydroxide solution cooled with ice, and twice with brine, then dried with magnesium sulfate, concentrated and purified on a silica gel chromatography column using a 1:9 ethyl acetate/petroleum ether mixture as eluent. 1c was isolated in the form of oil, which was crystallized in the refrigerator. Yield - 132.6g (7895).

Example 2. "3-(5-pyrimidyl)aniline (25). A suspension of 15 g (94.3 mmol) of 5-bromopyrimidine, 19.3 g (104 mmol) of 3-aminophenylboronic acid semisulfate, 39.6 mg (472 mmol) of sodium bicarbonate and 1 g of tetrakis(triphenylphosphine)palladium(0) in a mixture of 75 ml of water and 1500 ml of dimethoxyethane were heated to 807C under a stream of nitrogen overnight. After cooling, the mixture was poured into ice water, the precipitate was filtered, washed with water, dried and 15 g (9395) 205 was obtained. Melting point 164 - 16570.

Example 3. c 3-(1-imidazolyl)aniline (24), A mixture of 9 g (0.36 mol) of 1-iodo-3-nitrobenzene, 54 g (0.79 mol) of imidazole, 54 g (0.39 mol) of potassium carbonate and 1 g of highly dispersed copper was heated to 200". The melt was stirred for 2 hours under a layer of nitrogen. During the reaction, water vapor was retained by molecular sieves located between the reaction 2) vessel and the condenser. After the reaction, the mixture was cooled to 100"C and water was added. The mixture of 5p was cooled to room temperature, the crude product was filtered and dried. 54.2 g (79965) of 3-(1-imidazolyl) nitrobenzene was obtained by recrystallization from 200 ml of toluene. The melting point is 101 - 10270. 4) To a solution of 51.6 g (0.27 mol) of 3-(1-imidazolyl)nitrobenzene in 500 ml of acetic acid, a palladium catalyst (5 g of 590 Ra on activated carbon) was added and the mixture was hydrogenated under pressure (Rotand 4 bar) until hydrogen is no longer absorbed. The mixture was filtered through brownmillerite, the filtrate was evaporated to dryness and 40.4 g (9390) (24) were obtained as a light brown oil.

M-acetyl-3-(1-imidazolyl)aniline (2e). 5.88 g (37 mmol) of 24 was mixed with 3 mL of acetic anhydride at

F) at normal temperature for 1 hour. The mixture was poured into ice water and basified by adding 12M sodium hydroxide. The product was filtered off, washed with water and dried to give 6.34 g (8595) (2e). Melting point 181 - 18370. in Example 4. 3-(2-pyridyl)aniline (2. To a solution of 12.7 g (63.5 mmol) of 2-(3-nitrophenyl)pyridine (prepared as described in u). Spec. Zos. 1958, p. 1759) palladium catalyst (1.3 g of 595 Pa on activated carbon) was added to absolute ethanol, and the mixture was hydrogenated under normal pressure until hydrogen absorption stopped. The mixture was filtered through brownmillerite, the filtrate was concentrated under reduced pressure, and purified on a chromatographic 65 column with silica gel using a mixture of ethyl acetate/petroleum ether 1:9 as eluent to give 9.5 g (8890) (21) as a light brown oil.

5-(3-furanyl)-2-(3-carboxyphenyl)aminoaniline (13g) was obtained similarly from 12g (example 21). Ethyl acetate was used as an eluent for chromatographic treatment. Yield 9195. Melting point 211 -

Example 5. 2-(dimethylamino)pyrimidine. A solution of 5 g (43.65 mmol) of 2-chloropyrimidine in 5 mL of dry THF was saturated with gaseous dimethylamine. The mixture was stirred at room temperature for 1 hour, followed by evaporation of the solvent. The residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate.

The combined organic phase was dried with sodium sulfate and evaporated to give 5.07 g (9495) of product as a 7/0 brown oil. 5-bromo-2-(dimethylamino)pyrimidine. 5.07 g (41.22 mmol) of the above product was dissolved in glacial acetic acid (25 ml) and 2.15 ml (41.95 mmol) of bromine was added. The mixture was stirred at room temperature for 1 hour, poured into ice water and basified by adding 10M sodium hydroxide. The product was filtered, washed with water and dried, obtaining 4.72 g (5795) of the product. Melting point 162 - 16470. 3-(2-(dimethylamino)-5-pyridinyl)aniline (21). A mixture of 6.76 bg (33.17 mmol) of 5-bromo-2-(dimethylamino)pyrimidine, 7.Ag (39.78 mmol) of 3-aminophenylboronic acid hemisulfate, 13.73 g (99.49 mmol) of potassium carbonate, 12 ml (166 mmol) of 1-33-propanediol and 0.2 g of tetrakis(triphenylphosphine)palladium(0) in a mixture of 30 ml of water and 10 ml of dimethoxyethane was heated to 807C under a stream of nitrogen overnight. After cooling, the mixture was diluted with water and ethyl acetate and filtered through corrugated filter paper. Layers separated and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was triturated with ethyl acetate/petroleum ether 1:11 to give 5.26 g (7495) of crystals (21). Melting point 115.5 - 11776.

M-acetyl-3-(2-methylimidazol-1-yl)aniline, (2|1). 11 g (63.6 mmol) of 3-(2-methylimidazol-1-yl)aniline was added in portions to 100 ml of acetic anhydride at room temperature. After stirring for 1 hour. The mixture was poured into 300 ml of water. The resulting solution was cooled in an ice bath and made alkaline by adding 12M aqueous sodium hydroxide. The product was filtered off, washed with water and dried to give 12.Zg (9790) (21). and)

Melting point 238 - 24076.

Example 6. 1-(3-nitrophenyl)pyrrole. A mixture of 15 g (0.11 mol) of Z-nitroaniline, 42 ml (0.33 mol) of dimethoxytetrahydrofuran and the total catalytic amount of TOK in 175 ml of dry toluene was heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was purified on a chromatographic column with Me silica gel, using a mixture of ethyl acetate/petroleum ether 1:11 as an eluent, and 16 g (7890) of the product were obtained. Melting point 265 - 7076. 3-(1-pyrrolyl)aniline. To a suspension of 1bg (85.p.1 mmol) of the above product in 100ml of glacial acetic acid

To the acids, a palladium catalyst (1.5 g of 595 Pa on activated carbon) was added and the mixture was hydrogenated under pressure (Rotand 4 bar) until no more hydrogen was absorbed. The mixture was filtered through brownmillerite and the filtrate was evaporated to dryness. The obtained crude product was used in the next operation without purification.

M-acetyl-3-(1-pyrrolyl)aniline (2K). 4Oml of acetic anhydride was added to the above product at room temperature and stirred overnight. The mixture was poured into water. The crude product was filtered, washed with water and dried. Recrystallized from a mixture of water/ethanol 3:2, obtaining 9.93 g (5890) of pure (2K). more) s Melting point 134 - 13670.

Example 7. ;" 3-(2-aminopyrimid-5-yl)aniline (21). A mixture of 54 g (25 mmol) of 2-(acetamino)-5-bromopyrimidine, 5.58 g (30 mmol) of 3-aminophenylboronic acid hemisulfate, 10.4 g (75 mmol) of potassium carbonate, Uml (0.13 mmol) of 1,3- propanediol and 0.5 g of tetrakis(triphenylphosphine)palladium(0) in a mixture of 25 ml of water and 50 ml of dimethoxyethane were stirred at 807C under a stream of nitrogen overnight. After cooling, the mixture was poured into ice water.

The product (deacetylated in the reaction) was filtered off, washed with water and dried to give 4.19 g of 21 o (90905). Melting point 171 - 17276. 2) Example 8.

M-acetyl-M-(3-(1-imidazolyl)phenyl)-2-nitro-4-iodaniline (bs) Solution 2e from example C (30 g, 0.15 mol) in 200 ml of dry DMF was cooled to 0"С under a layer of nitrogen. 7.2 g of a 609° suspension of sodium hydride in 4) mineral oil was added in portions. After the evolution of hydrogen was stopped, a solution of 1c from example 1 (52 g, 0.19 mol) in 5 Oml of DMF was added. The mixture was stirred at 1207C for 5 hours and left for overnight at ambient temperature. The reaction mixture was poured into 4 volumes of water and the crude product was filtered off. Using a mixture of ethyl acetate and petroleum ether (3:17) as eluent, the product was purified on silica gel to give bs as an oil (7g, 2590).

Example 9.

F) IM-(3-(2-methyl-1-imidazolyl)phenyl)-2-nitro-4-iodaniline (bi). To the solution 2| from Example 5 (2g, 9.5 mmol) to 20ml of dry M-methyl-2-pyrrolidone was added in portions of 0.37g of a 6bO9o suspension of sodium hydride in mineral oil at 0"C. The mixture was stirred for 1 hour, the latter cooled at room temperature 1c from example 1bo (2, b7g, 10 mmol) was added and the temperature was increased to 40-50 "С during the night. After cooling, the mixture was poured into 4 volumes of water and extracted with dichloromethane. The organic phase was extracted with 4M hydrochloric acid. The acidic extract was cooled on ice, basified by adding 12M sodium hydroxide and extracted with dichloromethane. The organic phase was dried with magnesium sulfate and evaporated to dryness. The residue was extracted with a 1:1 mixture of dichloromethane and diethyl ether. The extract was concentrated under reduced pressure and dissolved in 65 bOml of dimethoxyethane. 28ml of 1M sodium hydroxide was added and the mixture was stirred at ambient temperature overnight.

The mixture was poured into 200 ml of water and a small volume of ethanol was added while stirring. The product was filtered, washed with water and dried, obtaining 2 g of bi (5195). Melting point 135 - 13670.

M-(3-(1-pyrrolyl. )phenyl)-2-nitro-4-iodaniline (6K) was obtained similarly from 1c (example 1) and 2K (example 6). Yield 30965, melting point 116 - 11870.

Example 10.

M-(3-(2-(dimethylamino)-pyrimid-5-yl)phenyl)-2-nitro-4-iodaniline hydrofluoride (61). A mixture of 1c from example 1 (3g, 11.2 mmol) and 2p from example 5 (2.4g, 11.2 mmol) in TOml of dry M-methyl-2-pyrrolidone was stirred under a layer of nitrogen at 120 - 135707 b hours. The mixture was cooled to room temperature and stirring was continued overnight. Water was added to the obtained suspension. The product was filtered off, dried and washed with ethyl acetate to obtain 6. (3.46 bg, 6490). Melting point 202 - 20376.

Hydrofluoride /- M-(3-(2-aminopyrimid-5-yl)phenyl)-2-nitro-4-iodaniline (61) was obtained similarly from 1c (example 1) and 2I (example 7). Yield 7995, melting point 236 - 23870.

IM-(3-(1-pyrazolyl)phenyl)-4-iodo-2-nitroaniline (bt) was obtained similarly from 1c (example 1) and 2t (example 75. 168). The base was released by treatment with sodium carbonate solution. Yield 2395, melting point 165 - 16676.

IM-(3-(2-methylthiazol-4-yl)phenyl)-4-iodo-2-nitroaniline (bp) was obtained similarly from 1c (example 1) and 2p (example 17). Yield 3295, melting point 137 - 13870.

IM-(3-(5-pyrimidyl)phenyl)-4-iodo-2-nitroaniline (65) was obtained similarly from 1c (example 1) and 25 (example 2). Yield 79795, melting point 214 - 21776.

IM-(3-(2-pyridyl)phenyl)-4-iodo-2-nitroaniline (6) was obtained similarly from 1c (example 1) and 27 (example 4).

Yield 4095, melting point 195 - 19670.

Example 11.

IM-(3-(1-imidazolyl)phenyl)-4-(3-furanyl)-2-nitroaniline (7c). A mixture of 17 g (38 mmol) bs from example 8, 5.6 g (30 mmol) of 3-furanylboronic acid, 15.7 g (0.11 mol) of potassium carbonate, 14 ml (0.17 mol) of 1,3-propanediol and

0.5 g of tetrakis(triphenylphosphine)palladium (0) in a mixture of bOml of water and 120 ml of dimethoxyethane was heated with a reflux condenser under a stream of nitrogen overnight. After cooling, the mixture was poured into 800 ml of water and stirred at 0°C until the precipitation of oily crystals was complete. The crude product (a mixture of acetylated and deacetylated) was filtered and dissolved in 200 ml of dimethoxyethane. ambient temperature. The mixture was poured into 500 ml of water, the product was filtered, washed with water and dried. Yield: 7790, melting point 147 - 14970. b"

M-(3-P-imidazolyl)phenyl)-4-(2-furanyl)-2-nitroaniline, (70) was obtained similarly from bs (example 8) and "9 2-furanylboronic acid). Yield 7795, melting point 147 - 149260.

Example 12. "

IM-(3-(2-methylimidazol-1-iluphenyl)-4-(3-furanyl)-2-nitroaniline (71). A mixture of g (2.38 mmol) bi from example 9, 0.4 g (3, 57 mmol) of 3-furanylboronic acid, 17 g (7.25 mmol) of potassium carbonate, 00 ml (11.2 mmol) of 1,3-propanediol and 5 mg of tetrakis(triphenylphosphine)palladium(0) in a mixture of 3.5 ml of water and 7/ml dimethoxyethane was heated under reflux under a stream of nitrogen for 4 hours.After cooling, the mixture was poured into

3 ml of water and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated under

Reduced pressure. The residue was purified on a silica gel column using a mixture of ethanol and ethyl acetate (1:4) as eluent. An oily product with a yield of 93905 was obtained. IM-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-4-(3-furanyl)-2-nitroaniline, (7p) was obtained similarly from bp a (example 10). Yield 8795, melting point 181 - 182760.

IM-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-4-(2-furanyl)-2-nitroaniline, (/t) was obtained similarly from bt (example 10) and 2-furanylboronic acid . Yield 89905, melting point 160 - 161 70. s M-(3-(1-pyrrolyl)phenyl)-4-(3-furan)-2-nitroaniline (7p) was obtained similarly from bp (example 9) and

Z-furanylboronic acid. Yield 8695, melting point 129 - 13176. ve IM-(3-(1-pyrrolyl)phent)-4-(2-furanyl)-2-nitroaniline, (7/K) was obtained similarly from bK (example 9) and

Ha 2-furanylboronic acid. Yield 83905, isolated as a brown-red oil.

IM-(3-(2-aminopyrimid-5-yl)phenyl)-4-(3-buranyl)-2-nitroaniline (7!) was obtained similarly from bi (example 10) and 3-furanylboronic acid. Quantitative yield, melting point 185 - 18670. 4) IM-(3-(2-aminopyrimid-5-yl)phenyl)-4-(2-furanyl)-2-nitroaniline (p) was obtained similarly from br (example 10) and 2-furanylboronic acid. Quantitative yield, melting point 178 - 18070. 1-(3-(5-pyrimidyl)phenyl)-5-(3-furanyl)-benzimidazole (95) was obtained similarly from 115 (example 15) and

Z-furanylboronic acid. For chromatographic purification, a mixture of dichloromethane and methanol (19:1) was used as an eluent. Yield 4895, melting point 216 - 21870.

F) 1-(3--2-methylthiazol-4-yl)phenyl)-5-(3-furanyl)-benzimidazole (9M) was obtained similarly from 11p (example 15) and 3-furanylboronic acid. For chromatographic purification, a mixture of ethyl acetate and petroleum ether (1:1) was used as an eluent. Yield 7395, melting point 136-138". in 1 -(34(1-pyrazolyl)phenyl)-5-(3-furanyl)-benzimidazole (9M) was obtained similarly from 11t (example 15) and

Z-furanylboronic acid. Yield 6495, melting point 170 - 17370. 1-(3-(-2-pyridyl)phenyl)-5-(2-furanyl)-benzimidazole (9) was obtained similarly from 117 (example 15) and 2-furanylboronic acid. Yield 4295, melting point 135 - 13670. 1-(3-(3-furanyl)phenyl)-5-(3-furanyl)-benzimidazole (94) was obtained similarly from 144 (example 15). 65 Yield-1595, melting point 170 - 17370.

IM-(2-(1-imidazolyl)pyridin-b-yl)-4-(3-furanyl)-2-nitroaniline (1bs) was obtained similarly from 1ba (example

25), excluding chromatographic treatment. The product crystallized quantitatively upon addition of water, melting point 173 - 17470.

Example 13.

IM-(3-(1-imidazolyl)phenyl)-2-amino-4-(3-furanyl)-aniline (8c) To a solution of 13g (37.6 mmol) of 7c from Example 11 in 25 ml of ethanol was added 6b.03g ( 113 mmol) of ammonium chloride and 27.05 g (113 mmol) of sodium sulfide nine hydrogen hydrate. The mixture was heated under reflux for 1 hour. After cooling, the mixture was poured into 700 ml of water. The product was filtered, washed with water and air-dried to obtain 8.7 g total with a yield of 73905.

Melting point 188 - 18976. 70 NM-(3-(2-imidazol-1-yl)phenyl)-2-amino-4-(33-furanyl)-aniline (8) was obtained similarly from 7| (example 12).

Quantitative yield, melting point 98 - 9976.

IM-(3-(1-pyrrolyl)phenyl)-2-amino-4-(3-furanyl)-aniline, (8K) was obtained similarly from 7K (example 12). Yield 8095, melting point 194 - 19576.

IM-(3-(1-imidazolyl)phenyl)-2-amino-4-(2-furanyl)-aniline (80) was obtained similarly from 70 (example 11). 7/5 Yield 9495, melting point 191 - 19470,

IM-(3-(1-pyrrolyl)phenyl)-2-amino-4-(2-furanyl)-aniline (8p) was obtained similarly from 7p (example 12). Yield 779Uo, melting point 163 - 16470.

IM-(3-(2--(dimethylamino)pyrimid-5-yl)phenyl)-2-amino-4-(3-furanyl)-aniline, (8j) was obtained similarly from 7p (example 12). Isolated as oil.

IM-(3-(2--(dimethylamino)pyrimid-5-yl)phenyl)-2-amino-4-(2-furanyl)-aniline (8t) was obtained similarly from 7t (example 12). Isolated as oil.

IM-(3-(1-pyrazolyl)phenyl)-2-amino-4-iodaniline (10t) was obtained similarly from bt (example 10). Yield 7590, melting point 134 - 13570.

IM-(3-(5-pyrimidyl)phenyl)-2-amino-4-iodaniline (105) was obtained similarly from bb (example 10). Yield 825965, s ob Melting point 166 - 16970.

IM-(3-(2-pyridyl)phenyl)-2-amino-4-iodaniline (107) was obtained similarly from bi (example 10). The product was i) used directly for further processing, see example 15.

IM-(3-(2-methylthiazol-4-yl)phenyl)-2-amino-4-iodaniline (101) was obtained similarly from bp (example 10). Yield 7390, melting point 151 - 15276. c zo M-(3-bromophenyl)-2-amino-4-(3-furanyl)-aniline, in a mixture with M-(3-iodophenyl)-2-amino-4- (3-Furanyl)-aniline (134) was obtained similarly from 124 (example 20). The mixture was isolated as an oil. Exit - 769090. b»

M-(3-(2-thiazolyl)phenyl)-2-amino-4-nitroaniline (200 was obtained similarly from 19Y (Example 27). Yield 967, "3 melting point 146 - 15970. Example 14.

IM-(3-(aminopyrimid-5-yl)phenyl)-2-amino-4-(-2-furanyl)-aniline (81). To the suspension 0.87g (2.33 mmol) 7p with "

From example 12, 0.1 g of palladium catalyst (595 Pa on activated carbon) was added to 1 ml of ethanol and the mixture was hydrogenated at normal pressure until hydrogen absorption stopped. The mixture was filtered through brownmillerite, which was washed successively with ethanol and DMF. The filtrate was evaporated under reduced pressure and the residue was triturated with water. The product was filtered, washed with water and dried in air, obtaining 0.5 g (63905) 8IP, melting point 211 - 21276.

IM-(3-(aminopyrimid-5-yl)phenyl)-2-amino-4-(3-furanyl)-aniline, (8p). 7! (example 12) were hydrogenated as described above with c. Exit 8 4395, melting point 208 - 20976.

Example 15. ;" 1-(3-(1-imidazolyl)phenyl)-5-(3-furanyl)benzimidazole (Us) A solution of 8.7 g (27.5 mmol) of 8c from example 13 in 100 ml of formic acid was heated under reflux for 30 minutes. After cooling, the mixture was poured into

ZbOml of water and made alkaline by adding 12M sodium hydroxide solution. The crude product was filtered, washed with water and dried in air. A solution of the crude product in a mixture of 200 ml of ethanol and 400 ml of dichloromethane was treated with activated charcoal under reflux for 30 minutes. The mixture was filtered through brownmillerite, and the filtrate was evaporated under reduced pressure until a precipitate appeared. Deposition was completed on ice

Oh bath. The product was filtered and dried. Yield: 7.5 g 8495, melting point 203 - 20476. 1-(3--2-(dimethylamino)pyrimid-5-yl)phenyl)-5-(3-furanyl)benzimidazole (9) was obtained similarly from 8p and ( example 13). Purification was carried out by chromatography on a silica gel column using a mixture of dichloromethane and acetone (9:1) as the eluent. Yield 3295 (from 7), melting point 183 - 18470. 1-(3--2-methylimidazol-5-yl)phenyl)-5-(3-furanyl)benzimidazole (9) was obtained similarly from 8) (example 13) .

Purification was carried out by chromatography on a column with silica gel using a mixture of two ethyl acetate and methanol (9:1) as an eluent. Yield 3295 (from 7p), melting point 183 - 1847С. 1-(3-(1-pyrrolyl)phenyl)-5-(3-furanyl)benzimidazole (9K) was obtained similarly from 8K (example 13). Cleaning

F) was performed by chromatography on a silica gel column using a mixture of ethyl acetate and petroleum ether (1:1) as an eluent. Yield 4296 (from 7!), melting point 144 - 14576. 1-(3-(-2-aminopyrimid-5-yl)phenyl)-5-(2-furanyl)benzimidazole (9) was obtained similarly from 8I (example 14 ). because Purification was carried out by chromatography on a column with silica gel using a mixture of ethyl acetate and methanol (9:1) as an eluent. Yield 1195, melting point 220 - 22276. 1-(3--2-(dimethylaminopyrimid-5-yl)phenyl)-5-(2-furanyl)benzimidazole (9t) was obtained similarly from 8t (example 13). Purification was carried out by chromatography on a column with silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as an eluent. Exit 42965 (from 7t). melting point 170 - 17276. 65 1-(3-(1-pyrrolyl)phenyl)-5-(2-furanyl)benzimidazole (9p) was obtained similarly from vp (example 13). Cleaning was carried out as for Ot. Yield 5395, melting point 137 - 13970.

1-(3-(1-imidazolyl)phenyl)-5-(2-furanyl)benzimidazole (90) was obtained in a similar way from vo (example 13). Cleaning was carried out as for 9s. Yield 4695, melting point 175 - 17776. 1-(3-(2-aminopyrimid-5-yl)phenyl)-5-(3-furanyl)benzimidazole (dr) was obtained similarly from 8p (example 14).

Purification was carried out as for 91. Yield 595 , melting point 222 - 22376. 1-(3-(5-pyrimidyl)phenyl)-5-iodobenzimidazole (115) was obtained similarly from 196 (example 13). The product was used without further purification. Yield 9195, melting point 197 - 19926. 1-(3--2-methylthiazol-4-yl)phenyl)-5-iodobenzimidazole (111) was obtained similarly from 10p (example 13). Yield 9895, melting point 163 - 16470. 70 1-(3-(1-pyrazolyl)phenyl)-5-iodobenzimidazole (11t) was obtained similarly from 10t (example 13). Yield 86965, melting point 209 - 21176. 1--3-(2-pyridyl)phenyl)-5-iodobenzimidazole (117) was obtained similarly from LO7 (example 13). Yield 53965, melting point 157 - 15870. 1-(3-bromophenyl)-5-(3-furanyl)benzimidazole in a mixture with 1-(3-iodophenyl-5-(3-furanyl)benzimidazole 144) 7/5 was obtained similarly from 134 (example 13). The crude product was used without purification (Example 12). Yield 4790. 1-(4-(1-imidazolyl)pyrimid-b-yl)-5-(3-furanyl)benzimidazole (185) was obtained similarly from 175 (example 26). Yield 2796 (from 165), melting point 294 - 29676. 1-(2-(1-imidazolyl)pyrimid-b-yl)-5-(3--furanyl)benzimidazole (18c) was obtained similarly from 17c (example 28) . The product was isolated by extraction and crystallization from ethyl acetate. Yield 2995, melting point 170 - 17876. 1-(3-(2-thiazolyl)phenyl)-5-nitrobenzimidazole (210) was obtained similarly from the 20th (example 13). Quantitative yield, melting point 251 - 26076.

Example 16. 1-(3-nitrophenyl)pyrazole. A mixture of 18.7 g (75 mmol) of 1-iodo-Z-nitrobenzene, 7.6 g (113 mmol) of pyrazole, 11.2 g (81 mmol) of potassium carbonate and a catalytic amount of cupric iodide and copper bronze in B5Oml of dry i)

M-methyl-2-pyrrolidone was heated to 1807 for 4.5 hours. After cooling, the mixture was filtered through brownmillerite.

The filtrate was poured into 7000 ml of ice water, the product was filtered, washed with water and dried, obtaining 13.57 g of product with a yield of 9695. Melting point 85 - 8770. s zo 3-(1-pyrazolyl)aniline (2t). A suspension of 5.5 g (34.6 mmol) of 3-(1-pyrazolyl)-nitrobenzene in BbbBOml of concentrated hydrochloric acid was heated under reflux. 24.2 g (0.11 mol) of Me chloride dihydrate was added in portions, continuing heating under reflux for another half hour. After cooling, the precipitate was filtered and dissolved in 200 ml of water. The resulting solution was cooled in an ice bath, made alkaline by the addition of 12M sodium hydroxide solution and extracted with ethyl acetate. The extract from 5 was washed with brine, dried over sodium sulfate and evaporated, obtaining the product in the form of a brownish oil. Output: Z.9g (7190). 1-(3-(2-thiazolyl)phenyl)-5-aminobenzimidazole (22) was obtained similarly from 21 (example 15). It was separated as an oil. Entrance; (659605).

Example 17. "3-(2-methylthiazol-4-yl)aniline (2n). A mixture of 5 g (20.5 mmol) of 2-bromo-3'-nitroacetophenone and 1.4 g (18.6 mmol) of thioacetamide in 5 mL of glacial acetic acid was heated under reflux overnight. After after cooling, the precipitate was filtered and washed with water and dried, obtaining 347 g (85965) and 2-methyl-4-(3-nitrophenyl)thiazole. Melting point 87 - 8870.

The product was hydrogenated as in example 4, quantitatively obtaining 2p. Melting point 80 - 8170.

Example 18. with M-acetyl-4-bromo-2-nitroaniline (14). A solution of 20 g (93.4 mmol) of 4-bromoacetanilide in methanesulfonic acid was cooled to 10°C. 12.bml of concentrated nitric acid was added and the mixture was stirred at 40°C for 2 hours. ve The mixture was poured into water with ice. The product was filtered, washed with water and dried. Output: 23.59g (97905). 2) Melting point 99 - 10070. 4-bromo-2-nitroaniline (17). A mixture of 33.5 g (13.5 mmol) of 14, 100 ml of dimethoxyethane and 5 ml of a 1 M sodium hydroxide solution was heated to 807C for 1 hour. The mixture was poured into ice water. The product was filtered, washed with water and dried. Output: 2.7 7g (9490). Melting point 109 - 11070.

Example 19.

M-acetyl-4-(3-furanyl)-2-nitroaniline (Te). A mixture of 8.5 g (32.8 mmol) and from example 18, C3.67 g (32.8 mmol)

Z-furanylboronic acid, 13.8 g (0.16 mol) of sodium hydrogen carbonate and 0.5 g of tetrakis(triphenylphosphine)palladium(0) in a mixture of 40 ml of water and 830 ml of dimethoxyethane were heated to 807C overnight

F) under a stream of nitrogen. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sulfate, and concentrated under reduced pressure (). The residue was dissolved in 40 ml of dimethoxyethane, 78 ml of 1 M sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. The mixture was poured into water and the solution was acidified by adding dilute hydrochloric acid. The precipitate was evaporated, washed with water and dried to give 5.09 g of Te (7695). Melting point 152 - 15476. 1-(3-(2-thiazolyl)phenyl)-5-(3-furanyl)-benzimidazole (93) was obtained similarly from 23Y (example 28) to ().

The residue was eluted through silica gel with a mixture of ethyl acetate and petroleum ether (1:1). Yield 995. Melting point 102 - 10570. 65 Example 20.

M-(3-bromophenyl)-4-(3-furanyl)-2-nitroaniline in a mixture with IM-(3-iodophenyl)-4-(3-furanyl)-2-nitroaniline

(124). A mixture of 2.65 ml (20.8 mmol) of 1-bromo-3-iodobenzene, 4 g (19.6 mmol) (1e) from Example 19, 2.93 g (21.2 mmol) of potassium carbonate and a catalytic amount of copper bronze in dry M-methyl-2-pyrrolidone was heated to 1807C overnight. After cooling, the mixture was poured into water, ethyl acetate was added, and the mixture was filtered through brownmillerite. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic extract was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified on a silica gel column with ethyl acetate and petroleum ether (1:29) as eluent. The mixture of products 124 was isolated in the form of 1.44 g of red oil, which was used directly in the next synthesis (see example 13). 70 Example 21.

M-(3-carboxyphenyl)-4-(3-furanyl)-2-nitroaniline (12g). A mixture of 5 g (24.5 mmol) (1e) from example 19, 6.69 ml (27 mmol) of 3-iodobenzoic acid, 3.79 g (27.5 mmol) of potassium carbonate and a catalytic amount of copper bronze in 30 ml of dry M-methyl- 2-pyrrolidone was heated to 1807C overnight. After cooling, water was added, and the mixture was washed twice with ethyl acetate. The aqueous phase was acidified with dilute hydrochloric acid and an oily precipitate was filtered off, which was extracted with ethyl acetate, and the extract was purified on a silica gel column with ethyl acetate and petroleum ether (1:1) as eluent. Yield: 2.65g (3295). Melting point 203 - 20576.

Example 22. 1-(3-carboxyphenyl)-5-(3-furanyl)-benzimidazole (14g). 25 mL of formic acid was added to 2.4 g (8.16 mmol) of 13 g from example 4 and the mixture was stirred at 807C for 1.5 hours. The cooled mixture was poured into ice water. The precipitate was filtered off, washed with methanol and dried, yielding 0.89g of 14g (4095). Melting point 272 - 2746. 1-(3-(3-(2-pyridyl)oxadiazol-5-yl)phenyl)-5-(3-furanyl)-benzimidazole (9g). A solution of 0.43 g (1.41 mmol) of 14 g in 1 ml of dry tetrahydrofuran was heated to reflux under a blanket of nitrogen. 0.4 g (2.48 mmol) of carbonyldiimidazole was added and heating was continued under reflux for 3 hours. 0.48 g (3.54 mmol) of 2-(oxymimido)pyridine was added and heated under reflux overnight. After cooling, the solvent i) was removed by evaporation and the precipitate was partitioned between water and ethyl acetate. The organic phase was dried with sodium sulfate and evaporated to dryness. The precipitate was dissolved in 15 ml of toluene, a catalytic amount of pTSK was added and heated under reflux overnight. The solvent was evaporated under reduced pressure and the residue was purified on a silica gel chromatography column with ethyl acetate and petroleum ether (1:1) as eluent. Yield 9g

Oh, 16g (2896). Melting point 183 - 18670. Me 1-(3--3-cyclopropyloxaiazol-5-yl)uphenyl)-5-(3-furanyl)-benzimidazole (95) was obtained similarly from 1.4 g and s of cyclopropyloxymide. Exit 1995. Melting point 144 - 14670.

Example 23. "2-Chloro-6-P-imidazolyl)pyridine 15a). A mixture of 5 g (33.78 mmol) of 2,6b-dichloropyridine, 2.3 g (33.78 mmol) of imidazole and 4.66 g (33.78 mmol) of potassium carbonate in 100 ml of DMF was heated to 857C overnight. The cooled mixture was poured into ice water and unreacted starting products were filtered. The filtrate was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The aqueous phase was basified by adding 10M sodium hydroxide solution and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, concentrated under reduced pressure and eluted through silica gel with ethyl acetate and methanol (9:1). After evaporation of the solvent, 0.16 g of 15a (28965) was obtained. Melting point 71 - 7370.

Example 24. ;" 4-Chloro-6-(1-imidazolyl)iupyrimidine (155). A mixture of 5 g (33.56 mmol) of 2,6-dichloropyrimidine, 2.3 g (33.56 mmol) of imidazole, and 4.63 g (33.56 mmol) of potassium carbonate in HOml of DMF was stirred at room temperature for

Nights The mixture was diluted with four volumes of water and extracted with dichloromethane. The organic extract was concentrated under reduced pressure and eluted through silica gel with ethyl acetate and methanol (9:1). After evaporation of the solvent and trituration of the residue in a mixture of diethyl and petroleum ethers (1:1), 4.07 g of 156 (6795) was obtained. Melting point 198 - 20070. 2) Example 25.

IM-(2-(1-imidazolyl.)pyridin-6b-yl)-4-bromo-2-nitroaniline (1ba). 0.5 g of 60905 suspension of sodium hydride in mineral oil was added to a solution of 2.7 g (12.5 mmol) of Example 1 and 18 in 25 ml of dry DMF and the mixture was stirred for 30 4) minutes. 2.25 g (12.5 mmol) of 15a from example 23 was added and the mixture was heated at 1007C overnight. The cooled mixture was poured into ice water and the precipitate was filtered off, which was dried and redissolved in ethyl acetate. The filtrate was extracted with ethyl acetate. The combined product solutions were concentrated and purified on a silica gel column chromatography with ethyl acetate and methanol (9:11) as eluent. After evaporation of the solvent and trituration of the residue with a mixture of diethyl and petroleum ethers (1:11), 0.93 g of 1ba (2195) was obtained. Temperature (F, melting 194 - 195760. ka IM-(4-(1-imidazolyl)pyrimid-b-yl)-4-(3-furanyl)-2-nitroaniline (165) was obtained similarly from 1560 and Te. As an eluent ethyl acetate was used for chromatographic treatment. Yield 2395. Melting point 198 - 200.

Example 26.

1N-(4-(1-imidazolyl)pyrimid-b-yl)-2-amino-4-(3-furanyl)-aniline (175). A suspension of 0.23 g (1.1 mmol) of 166 (example 25) in a mixture of ethanol and dichloromethane was hydrogenated at room temperature using nickel

Raney (5095 sludge in water) as a catalyst. After complete absorption of hydrogen, the mixture was filtered through 65 brownmillerite, the filtrate was evaporated and 17p was obtained as an oil, which was used without purification.

IM-(2-(1-imidazolyl)pyrid-b-yl)-2-amino-4-(3-(furanyl)-aniline, (17s). Suspension 0.9g (266 mmol) 16s

(example 12) in bOml mixture of ethanol and dichloromethane (4:11) was hydrogenated at room temperature using 0.15 g of palladium catalyst (595 on activated carbon). After completion of water absorption, the mixture was filtered through brownmillerite, the filtrate was evaporated and 17c was obtained as an oil, which

Used without cleaning.

Example 27.

IM-(3-(2-thiazolyl)phenyl)-2,4-dinitroaniline (199. A mixture of 1.14 ml (9.1 mmol) of 2,4-dinitrofluorobenzene, 1.6 bg (9.1 mmol) of 2 from example 2, 1 .51 g (10.9 mmol) of potassium carbonate in 10 ml of dry M-methyl-2-pyrrolidone was heated to 80"C for 2 hours. The cooled mixture was poured into ice water. The precipitate was filtered, washed with 7/0 water and dried, obtaining C .05g (98965). Melting point 197 - 20370.

Example 28. 1-(3-(2-thiazolyl)phenyl)-5-iodobenzimidazole (230). A suspension of 0.85 g (2.91 mmol) of 221 from example 16 in hydrochloric acid was cooled to -57C. A solution of 0.22 g (3.2 mmol) of sodium nitrite in 3 ml of water was added dropwise, keeping the temperature below 0"C. Then the mixture was stirred at (-5-0)"C for 20 minutes. A solution of potassium iodide (3.64 mmol) in 7/5 ml of water was added and the mixture was stirred at room temperature overnight. Aqueous sodium sulfite was added to the reaction mixture until the iodine color disappeared. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with aqueous sodium carbonate, dried with sodium sulfate and filtered through silica gel. The filtrate was evaporated to dryness, obtaining 23. Yield 2395. Melts with decomposition at 17570.

Example 29.

M-(3-iodophenyl)-4-cyano-2-nitroaniline (29). To a solution of 1.82 g (10 mmol) of 4-chloro-Z-nitrobenzonitrile in 25 mL of dry DMF, 1.54 mL (11 mmol) of triethylamine and 1.2 g (10 mmol) of Z-iodaniline were added and the mixture was heated to 80-1007C overnight. The cooled mixture was poured into four volumes of water with ice. The precipitate was filtered, washed with water and dried. The crude product was washed with hot ethanol, obtaining 2.1 g (5895) of the title compound. Melting point 211 - 21276.

Example 30. (8) 2-amino-(M-(3-iodophenyl)-4-cyanoaniline (30). To a suspension of 2.1 g (5.75 mmol) of 29 in 5 bml of methanol was added 0.92 g (17.25 mmol ) of ammonium chloride and 4.14 g (17.25 mmol) of sodium sulfide ninehydrate and heated the mixture under reflux for 1.5 hours. The cooled mixture was poured into 2000 ml of ice water. The precipitate was filtered off, washed with water and dried, obtaining 1 .8 g (93956) of the title compound. Melting point 170 - 17276. b"

Example 31. c 5-cyano-1-(3-iodophenyl)-benzimidazole (31). A suspension of 1.8 g (5.36 mmol) of 30 in 20 Oml of formic acid was heated to 80 - 1007 for 1.5 hours. The hot reaction mixture was filtered through a cotton swab into 100 ml of ice water. The precipitate was filtered, washed with water and dried. The crude product was dissolved in dichloromethane and precipitated by adding petroleum ether. The product was filtered and dried to give 1.38g (7590) of the title compound. Melting point 177 - 17976.

Example 32. 5-cyano-1-(3-(3-pyridyl)phenyl)-benzimidazole (32a). Mixture 4g (11.66 mmol) 31, 2.04g (13.9 mmol) «

Z-pyridylborane, 4.8 g (34.8 mmol) of sodium bicarbonate and 0.2 g of tetrakis(triphenylphosphine)palladium(0) in a mixture with 20 Oml of water and dimethoxyethane were heated to 807C overnight under a stream of nitrogen. After cooling, the obtained

And the suspension was poured into water and the crude product was filtered, washed with water and dried. The cleaning was carried out on chromatographic silica gel column with ethyl acetate and methanol (9:1) as an eluent. Yield of the title compound 2.46 g (72965). Melting point 191 - 19370.

Example 33. c 2-tributylstannyl(thiazole) (33). To a solution of 0.71 ml (10 mmol) of thiazole in 20 ml of dry THF, 6 b.9 ml (11 mmol) of 1.6 M butyllithium in hexane was added dropwise under a layer of argon at -78"C. The reaction mixture was stirred at -787C for 0.5 hours and added 3.1 ml (11 mmol) of VizZpsiI dropwise. After stirring at -78"C for 1 hour and 12) hours at room temperature, the mixture was concentrated, triturated with 50 ml of water and extracted three times with 100 ml of diethyl ether. The extract was washed with brine, dried and concentrated under reduced pressure, obtaining a quantitative yield of 3.7 g of 33 as a colorless oil. 4) Example 34. 5-acetyl-1-(3-(2-thiazolyl)uphenyl)benzimidazole (34). 1.5 g (4.8 mmol) of 5-acetyl-1-(3-bromophenyl)benzimidazole and 34Omg (0.48 mmol) of (PPI)DRasi were added to a solution of 3.bg (9.7 mmol) 33 in 2000 ml of dry THF under a layer of argon. The reaction mixture was stirred at 807C for 24 hours in a sealed vessel. After cooling, the mixture was concentrated, triturated with 100 ml of water and extracted three times with 200 ml of dichloromethane. The extract was washed

F) brine, dried and concentrated under reduced pressure. The residue was washed with ether, obtaining 1.5 g (89965) 34 in the form of crystals. 5-Acetyl-1-(3-bromophenyl)benzimidazole was obtained as described below. in 4-acetyl-2-nitroaniline. 26.5 g (11.94 mmol) of M-(4-acetyl-2-nitrophenyl)acetamide was added to 50 ml of a mixture of water and concentrated sulfuric acid (1:2). After 15 minutes, the mixture was poured into water. The product was filtered, washed with water and dried.

M-(3-bromophenyl)-4-acetyl-2-nitroaniline. A mixture of 3.41 g (18.94 mmol) of 4-acetyl-2-nitroaniline, 4.bml (38.06 mmol) of 1,3-dibromobenzene, 2.62 g (19 mmol) of potassium carbonate and a catalytic amount of copper bronze was heated to 65 18072 and stirred under a stream of nitrogen for 2 days. After cooling, the solid reaction briquette was extracted with a mixture of dichloromethane and methanol (9:1). The extract was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was eluted through silica gel with a mixture of petroleum ether and ethyl acetate (4:11) to give 0.67g (10.696) of pure product. Melting point 142 - 14476, 5-acetyl-1-(3-bromophenyl)benzimidazole. 9.0 g (26.63 mmol) of N-(33-bromophenyl)-4-acetyl-2-nitroaniline was suspended in 100 ml of 9995 ethanol. Raney nickel was added and the mixture was hydrogenated at normal pressure for 20 hours.

Chloroform was added. The mixture was filtered through brownmillerite and evaporated in vacuo to give 8.03 g of an oil to which 8 mL of formic acid was added and the mixture was heated to 807°C for 1.5 h. The excess formic acid was removed in vacuo. The residue was mixed with water and the solution basified by adding of 7/0 sodium hydroxide The product was filtered off, washed with water and dried.

Example 35. 5-cyano-1-(3-(2-thiazolyl)phenyl)benzimidazole (35) was synthesized as in example 34 using instead of 5-acetyl-1-(3-bromophenyl)benzimidazole 2.0 g (5.9 mmol) 31.100mg (0.14 mmol) (PPRI)"Rasi" and 33.bg (9.7 mmol) of 2-(tributylstanyl)thiazole. The reaction yielded 1.5 g (8690) of 5-cyano-1-(3-(2-thiazolyl)phenyl)benzimidazole.

Example 36. 4-(Z-nitrophenyl)pyrimidine (36). A mixture of 10.0 g (64 mmol) of 4-phenylpyrimidine and 33 ml of concentrated M2804 was added to a mixture of 22 ml of concentrated NaSO); and 1 bml of concentrated NMO3 at 0"C. The resulting mixture was stirred at 07C for 2 hours, poured onto crushed ice and extracted with dichloromethane. The extract was washed with 595% aqueous solution of NaCl, dried over NaCl, and concentrated under reduced pressure. The residue was triturated with isopropanol and the precipitate was filtered and dried under reduced pressure to give 6.4 g (5090) 36.

Example 37. 4-(33-Aminophenyl)pyrimidine (371) To a suspension of b,3g (31 mmol) 36 in a mixture of bbOml MeonH and 30ml THF was added

ZOOmg 595 palladium on activated carbon, the mixture was hydrogenated at normal pressure for 1 hour, filtered and concentrated under reduced pressure. The residue was purified on a chromatographic silica gel column with ethyl acetate and hexane (1:3) as an eluent to obtain 5.1 g (9690) 37. i)

Example 38.

IM-(3-(4-pyrimidyl)phenyl)-4-cyano-2-nitroaniline (38). To a mixture of 5.5 g (30 mmol) of 37 and 5.1 g (30 mmol) of 4-chloro-3-nitrobenzonitrile in 120 ml of THF was added 2.3 g of 5095 suspension of sodium hydride in mineral oil. After stirring for 2 days at room temperature, the mixture was poured into water and extracted with dichloromethane. The extract was concentrated under reduced pressure and the residue was triturated with diethyl ether to obtain 9.2 g (9695) of crystalline 38.s

Example 39.

IM-(3-(4-pyrimidyl)phenyl)-4-cyano-2-aminoaniline (39) was synthesized as described in example 37, using instead of 4-(3-nitrophenyl)pyrimidine 9.2 g (29 mmol) 38 and bO0g of the catalyst. 8.3 g of 38 was quantitatively obtained by the reaction,

Example 40. 5-cyano-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (40). A mixture of 3.0 g (10 mmol) 39 and 20 ml of formic acid was stirred at 11072 for 1 hour and concentrated in a vacuum. The residue was distributed among 596 aqueous solutions

Manso" and SNoSi". The organic phase was dried with magnesium sulfate and the solvent was removed by evaporation. The residue from c was triturated with ethyl acetate to give 2.6 g (8590) of crystalline 40.

Example 41. ;" 5-formyl-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (41 a). 2.2 g of Raney nickel was added to a solution of 3.9 g of 40 in a mixture of 48 ml of formic acid and 13 ml of water. The mixture was stirred at 1007°C for 0.5 hours under argon. After cooling, the mixture was filtered. The filtrate was concentrated and partitioned between TM aqueous Manso solution and ethyl acetate. The ethyl acetate extract was washed with brine, dried and concentrated under reduced pressure to obtain 2.7 g ( 6995) crystalline 41a and 5-formyl-1-(3-(2-thiazolyl)phenyl)benzimidazole (415) were obtained similarly from 35, 2) 5-formyl-1-(3-(1-imidazolyl)phenyl)benzimidazole (41c) was obtained similarly from 3260. 5-formyl-1-(3-(3-pyridyl)phenyl)benzimidazole (414) was obtained similarly from 32a.se) Example 42. 4) Oxime 5-formyl-1-(3- (4-pyrimidinyl)phenyl)benzimidazole (42a). 2.7 g of 41a was added to a mixture of 100 ml of ethanol, 1.9 g of MNON Nei (3 equivalents) and 1.3 ml of triethylamine (1 equivalent). The mixture was stirred for 1 hour at 60C, cooled to 0"C, the precipitate was filtered off, washed with water and dried under reduced pressure, obtaining 2.2 g of two (TT) 42a.

5-Formyl-1-(3-(2-thiazolyl)phenyl)benzimidazole oxime (425) was obtained similarly from 416,

F) 5-Formyl-1-(3-(1-imidazolyl)phenyl)benzimidazole oxime (42c) was obtained similarly from 41c, and 5-formyl-1-(3-(3-pyridyl)phenyl)benzimidazole oxime (424) received similarly from 414.

Example 43. in 5-(3-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (43a). A mixture of 2.1 g of 42a and 1.1 g (1.2 equivalents)

M-chlorosuccinimide in 100 ml of DMF was stirred at 607"C for 0.5 hour under argon. While cooling with ice, 25 ml of vinyl bromide was added to the reaction mixture, then 4.8 ml (5 equivalents) of triethylamine in 15 ml of DMF was added dropwise over 1 hour. The mixture was stirred at 07C for 3 hours and at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried b5 and concentrated under reduced pressure. The residue was purified on a silica gel chromatography column with dichloromethane and methanol (30:11) in quality eluent with 1.5 g (64965)

5-(3-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole. Melting point 214 - 21576. 5-(3-isoxazolyl)-1-(3-(2-thiazolyl)phenyl)benzimidazole (435) was obtained similarly from 420. melting point 157 - 15870. 5-(3-isoxazolyl)-1 -(3-(1-imidazolyl)phenyl)benzimidazole (43c) was obtained similarly from 42c. melting point 230 - 23476. 5-(3-isoxazolyl)-1-(3-(3-pyridyl)phenyl)benzimidazole (434) was obtained similarly from 424, melting point 208 - 21070.

Example 44. 70 5-acetyl-1-(3-(3-pyridyl)phenyl)benzimidazole (44a). 4-fluoro-3-nitroacetophenone. 200ml of concentrated sulfuric acid was cooled to 57"C and 20ml (154.76 mmol) of 4-fluoroacetophenone was added without raising the temperature above 10"C. The mixture was cooled to 0 - 5"C and 25g (247.146 mmol) of potassium nitrate was added in portions over 2 hours, maintaining the temperature at 0 - 570C. Then the mixture was stirred at this temperature for another 2 hours, poured onto a bag of ice and the crude /5 product was filtered. Purification on a chromatographic silica gel column with ethyl acetate and petroleum ether (1:9) as an eluent, 18.19 g (6095) of pure 4-fluoro-3-nitroacetophenone was obtained. 3-(3-pyridyl)nitrobenzene. To 8.53 g (54 mmol) 10 g (59.95 mmol) of 3-nitrophenylboronic acid, 30 ml of 1 M aqueous potassium carbonate and 0.5 g (0.43 mmol) of tetrakis(triphenylphosphine)palladium were added to 3-bromopyridine in 180 ml of ethylene glycol dimethyl ether. The mixture was gently heated with refluxed overnight under a 2o stream of nitrogen. After cooling, the mixture was filtered and bOOml of water was added to the filtrate. The precipitate was filtered off and washed with water. This crude product was dissolved in 400ml of hot water with the addition of 25ml of 4M hydrochloric acid. The mixture was filtered while hot. The filtrate was cooled and in an ice bath and pure 3-(3-pyridyl)nitrobenzene was precipitated by adding 12M Mahon. Output: 9.14g (85960). 3-(Z-pyridyl)aniline. 9.1 g (45.5 mmol) of 3-(3-pyridyl)nitrobenzene in 125 ml of ethanol was hydrogenated at normal atmospheric pressure for 1.75 hours using Raney nickel as a catalyst. 3-(3-pyridyl)aniline was quantitatively obtained by filtering the resulting solution through brownmillerite followed by evaporation of the solvent. i) 4-acetyl-2-nitro-IM-(3-(3-pyridyl)phenyl)aniline. A mixture of 5 g (27.3 mmol) of 4-fluoro-3-nitroacetophenone and 4.62 g (27.2 mmol) of 3-(3-pyridyl)aniline in 10 ml of dry M-methyl-2-pyrrolidone was heated to 40 - 507"C overnight.

The obtained solid reaction mixture was suspended in BbBOml of water and alkalized with 1M Mansoz. The product was filtered off, washed with water and dried, obtaining 7.68 g (8590) of 4-acetyl-2-nitro-N-(3-(3-pyridyl)phenyl)aniline. Mes-acetyl-2-(3-(3-pyridyl)phenyl)aminoaniline. 2 g (6 mmol) of 4-acetyl-2-nitro-Mm-(3-(3-pyridyl)phenyl)aniline was suspended in a mixture of bOml of ethanol and 1Oml of dichloromethane and hydrogenated at normal pressure using 596 palladium on activated carbon as a catalyst. Filtration of the resulting solution through brownmillerite followed by evaporation of the solvent yielded an oil, which after trituration with a mixture of diethyl and petroleum ethers (1:1) gave 1.46 g (8095) of pure 5-acetyl-2-(3-(3-pyridyl) )phenyl)aminoaniline. 5-acetyl-1-(3-(3-pyridyl)phenyl)benzimidazole. 5 Bg (16.5 mmol) of 5-acetyl-2-(3-(3-pyridyl)phenyl)aminoaniline in Bbml of formic acid was stirred for 1.5 hours at 907С. The cooled reaction mixture was alkalized with 12 M of ammonium. β5-acetyl-1-(3-(3-pyridyl)phenyl)benzimidazole was filtered, washed with water and dried. Quantitative yield, melting point 195 - 9776. with 5-acetyl-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (4456).

Example 45. ;" 5-(5-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (45a) was obtained as follows: 5-(3-dimethylamino-1-oxo-2-propen-1-yl)-1- (3-(4-pyrimidinyl)phenyl)benzimidazole. 314 mg (445) was reacted with ml of dimethylacetal DMF in 3 ml of DMF for 5 hours at 1207C under a layer of argon. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was purified on a chromatographic silica gel column with dichloromethane and methanol (30:11) as eluent Kk) to obtain 320 mg (8790) 2) 5-(3-dimethylamino-1-oxo-2-propen-1-yl)-1- (3-(4-pyrimidinyl)phenyl)benzimidazole. 5-(5-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole. A mixture of 307 mg of 5-(3-dimethylamino-1-oxo-2-propen-1-yl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole and 13 mg (2.5 equivalents) in 4) 14 ml of methanol was stirred for 2 hours at 80°C. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane and methanol (40:1, by volume) as eluent) ) to obtain 226 mg (8096) 5-(5-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole. 5-(5-isoxazolyl)-1-(3-(2-thiazolyl)phenyl) benzimidazole (455) was obtained similarly from 34. temperature (F, melting point 186 - 887. ka 5-(5-isoxazolyl)-1-(3-(3-pyridyl)phenyl)benzimidazole (45c) was obtained similarly from 44a, melting point 218 - 21970. The compounds obtained in the above examples are presented in the following tables 1 and 2.

Table 1

Mo spol Ag O A in furan-substitute. plot T.pl. (C") App. 9c 1-imidazolyl sn snsn C 203-204 15 65 Op O/02 - (dimethylamino)-5-pyrimidyl CH CH CH 3 183-184 15 9i 2-methyl-1-imidazolyl sn snsn C 105 -107 15

OKO 1-pyrrolyl sn sn osn Z 144-145 15 9I 2-amino-5-pyrimidyl sn snsn 2 220-222 15

Zt 2-(dimethylamino)-5-pyrimidyl and CH CH CH 2 170-172. 15

Op 1-pyrrolyl sn sn 2 137-139. 15 90 1-imidazolyl sn sn osn 2 175-177. 15

OR /2-amino-5-pyrimidyl sn snsn Z 222-223 15

Or B-pyrimidyl sn sn sn Z 216-218. 12

ЗМ 0 2-methyl-4-thiazolyl сн сн сн 3 136-138 12 70 9М /1-pyrazolyl сн сн осн С 170-173. 12

Ogo 2-pyridyl sn sn osn 2 135-136. 12 94 / Z-furanil sn sn osn Z 149-150. 12

Zgo00/ 3-(2-pyridyl)-oxadiazol-b-yl. СН СН Сн 3 183-186 22 985 / Z-cyclopropyloxadiazol-B-il. СН СН сн 3 144-146 22 90 2-thiazolyl сн сн осн З 102-105. 19 185. 1-imidazolyl sn M m Z 294-296. 15 18c 1-imidazolyl M сн осн З 170-173 175

Table 2

Ag isoxazole-substituent. plot T.pl. (C") Example

B-pyrimidyl Z 214-215 4Z

Z-pyridyl Z 208-210 4Z 2-thiazolyl 3 157 - 158 43 si 1-midazolyl Z 230-234 43 2-thiazolyl B 186 - 188 45 i9)

Z-pyridyl 5 218-219 45 so

Claims (1)

The formula of the invention F co 1. The compound of the formula: Е « ve iv) o MU M « x EZ - s or its pharmaceutically acceptable salt or oxide, where в3- " XX pk Ii; its also, their in VE s where each A, B and 0 - CH, or one or two A, B and O - M, and the others - CH; B"! - phenyl, benzimidazole or monocyclic heteroaryl, each of which may be substituted by one or more substituents selected from alkyl, alkoxyl, phenyl, halogen, SE3, amino-, nitro-, cyano-, acyl, se» acylamino groups, phenyl, and monocyclic heteroaryl, and one of B5 and B is hydrogen, the other is furanyl or isoxazolyl, each of which may be substituted one or more times with substituents selected from halogen, alkyl, alkyl, and phenyl. 2. The compound according to claim 1, which differs in that it is: 1-(3-(1-imidazolyl)phenyl)-5-(3-furanyl)benzimidazole and) 1-(3--2-methyl-1-imidazolyl) )phenyl)-5-(3-furanyl)benzimidazole or 1-(3-(5-pyrimidinyl)phenyl)-5-(3-furanyl)benzimidazole or their pharmaceutically acceptable salt or oxide. 60 Z. The compound according to claim 1, which differs in that it is: 1-(3--2-(dimethylamino)pyrimid-5-yl)phenyl)-5-(3-furanyl)benzimidazole 1-(3-(1 -pyrrolyl)phenyl)-5-(3-furanyl)benzimidazole 1-(3-(-2-aminopyrimid-5-yl)phenyl)-5-(2-furanyl)benzimidazole 1-(3--2-(dimethylaminopyrimide) -5-yl)phenyl)-5-(2-furanyl)benzimidazole 65 1-(3-(1-pyrrolyl)phenyl)-5-(2-furanyl)benzimidazole 1-(3-(1-imidazolyl)phenyl) -5-(2-furanyl)benzimidazole 1 -(3-(-2-aminopyrimid-5-yl)phenyl)-5-(3-furanyl)benzimidazole 1-(4-(1-imidazolyl)pyrimid-b-yl)-5-(3-furanyl) benzimidazole 1-(2-(1-imidazolyl)pyrimid-b-yl)-5-(3-furanyl)benzimidazole 1. -(3-(2-thiazolyl)phenyl)-5-(3-furanyl)-benzimidazole 1 -(3--2-methylthiazol-4-yl)phenyl)-5-(3-furanyl)-benzimidazole 1 -(3-(1 -pyrazolyl)phenyl)-5-(3-furanyl)-benzimidazole 1-(3-(2-pyridyl)phenyl)-5-(2-furanyl)-benzimidazole 1-(3-(3 -furanyl)phenyl)-5-(3-furanyl)-benzimidazole 70 1-(3-(3-(2-pyridyl)oxadiazol-5-yl)phenyl)-5-(3-furanyl)-benzimidazole 1-( 3-"3-cyclopropyloxadiazol-5-yl)phenyl)-5-(3-furanyl)-benzimidazole 5-(3-isoxazolyl)-1. -(3-(4-pyrimidinyl)phenyl)benzimidazole 5-(3- isoxazolyl)-1 -(3-(2-thiazolyl)phenyl)benzimidazole 5-(3-isoxazolyl)-1-(3-(1-imidazolyl)phenyl)benzimidazole 5-(3-isoxazolyl)-1 -(3- (Z-pyridyl)phenyl)benzimidazole 5-(5-isoxazolyl)-1.-(3-(4-pyrimidinyl)phenyl)benzimidazole 5-(5-isoxazolyl)-1-(3-(2-thiazolyl)phenyl) benzimidazole or 5-(5-isoxazolyl)-1-(3-(3-pyridyl)phenyl)benzimidazole or a pharmaceutically acceptable salt or oxide thereof. 4. A pharmaceutical composition containing an effective amount of a compound according to any one of claims 1-3, or a pharmaceutically acceptable addition salt or oxide thereof together with a pharmaceutically acceptable carrier or diluent. 5. A method of treating disorders of the central nervous system or diseases of living organisms of animals, including humans, sensitive to the positive modulation of GABA d-receptor complexes, which includes the use, if necessary, of such living organisms of animals, including humans, of a therapeutically effective amount of the compound according to any of the claims 1-3. (8) 6. The method according to claim 5, which differs in that it is used for the treatment of disorders or diseases sensitive to positive modulation of GABA-receptor complexes. 7. The method according to claim 5, which differs in that it is used for the treatment of anxiety states, disorders with ZobnU, memory, epilepsy or other convulsive disorder. 8. The method according to claim 5, which is characterized by the fact that the active ingredient is used in the form of a pharmaceutical Me composition, in which it is together with a pharmaceutically suitable carrier or diluent. s " IS c) shi s with 1 sh" (95) o 50 syu" F) ime) 60 b5